Bicyclo-(2.2.1)-hept-5-ene-2-carbinyl-nicotinate



United States Patent 3,185,697 BICYCLO-(Z.2.1)-HEPT--ENE-2-CARBENYL- NICOTINATE Perttu V. Laakso, Tower Lakes, Barrington, Ill., assignor to The Kendall Company, Boston, Mass, a corporation of Massachusetts No Drawing. Filed Aug. 21, 1961, Ser. No. 132,545

1 Claim. (Cl. 260-2955) This invention relates to a new analgesically active compound and compositions containing the compound suitable for use in the treatment of muscular aches and pains.

Analgesic compositions are topically applied in the treatment of muscular soreness due to muscular bruises, sprains and the like. Although the exact mechanism by which these compositions exert their pain-relieving effect is not fully understood, there is general agreement that the active agents in the analgesic compositions must be capable of passing through the skin and effect a vasodilation in the skin and deeper tissues. It has been shown that vasodilation is brought about by stimulation of nerve fibers which cause a dilating response in the arterioles and precapillary arteriolar sphincters. Capillaries and non-muscular venules do not dilate, but because of the arteriolar dilation have an increase in flow rate with a small accompanying distension. In addition, some capillaries previously devoid of blood become filled.

The increase in the supply and flow of blood removes toxins and metabolites in the treated areas. The new blood in the treated areas also bring in a' supply of nutricuts. The removal of toxins and metabolites and the supply of nutrients contribute to relief of muscular soreness and pain. I The vasodilating efiect of analgesically active compounds is accompanied by an increase in the temperature of the skin and erythemic reaction (redness). These changes of temperature and color of the skin can be observed and serve as a measure of the vasodilatory activity of the analgesically active compounds.

The intensity of the change in skin temperature induced by the compounds should not be so great as to be uncomfortable for the patient. Generally, a chemically induced increase in skin temperature of several degrees is tolerable. A large increase in temperature does not in itself quality a compound as a suitable ingredient for analgesic composition. The length of time of the chemically induced vasodilation is of considerable importance. The new compound of this invention is bicyclo-(2.2.1)- hept 5 ene 2 car binylnicotinate. This nicotinate ester (occasionally referred to hereafter simply as the bicyclo nicotinate) produces a comfortable sensation of warmth when applied to the skin, producing an increase in temperature of between about 3 F. to 4 F. in the skin within about the first half hour after application. The temperature of the skin then gradually decreases, and after about 3 hours is still approximately 1 F. higher than other comparable skin portions of the body. A condition of erythema remains for as long as 24 hours after application, indicating increased blood flow and supply in the region of the treated area.

Advantageously, the bicyclo (2.2.1) hept 5 ene 2- carbinylnicotinate is substantially less odoriferous than many of the presently commercially used analgesically active compounds.

The bicyclo-(2.2.1)-hept-S-ene-Z-carbinylnicotinate may be compounded with various carriers normally used in liniment and balm formulations.

The activity of the bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate as an analgesic compound can be objectively illustrated by the occurrence of erythema and rise in temperature. of the skin in the locale of application. This 3,185,697 Patented May 25, 1965 activity and comparison thereof with other compounds is hereinafter illustrated.

ERYTHEMA The chemical tested was applied on the inner aspect of the forearm over a previously marked-out one square inch area. The degree of erythema produced was then evaluated at various intervals according to the following scale:

0--no erythema l-slight erythema 2-clear erythema 3strong erythema I 4very strong erythema All observations of erythema intensity were made by the same person in order to make the rating objective. Hyperactive and hypoactive individuals were eliminated from the study. No one individual was used as a test subject in less than 4 days before testing again.

In each of the tests tabulated in Table I the vehicle for the analgesically active compound was a 50% mixture of isopropanol in water. The active compounds were present in an amount 5% by weight of the total mixture. The control was the 50% mixture of isopropanol in water.

1 S'Iim'e after application at which erythema rating at least In all instances the skin remained uncovered. The methyl salicylate (more commonly known as oil of wintergreen) produced only a very minor amount of erythema. The bicyclo nicotinate compound of this invention produced a greater amount of erythema than either of the two commonly used analgesically active compounds: methyl nicotinate and methyl salicylate. Most significantly, however, the bicyclo nicotinate ester produced a greater effect for a much longer period of time than either of the other compounds.

Furthermore, the activity of this bicyclo nicotinate ester is greater than the activity of formulations contain ing mixtures of methyl nicotinate and methyl salicylate either together or with other ingredients to complement the analgesic function of these two compounds. The liniment solution containing 5% bicyclo-(2.2.l)-hept-5- ene-Z-carbinylnicotinate in the isopropanol-water carrier I was also compared with several commercial analgesic preparations. The measurements of erythema were made in the manner described above. Again the compound of this invention exhibited a greater degree and duration of 'erythemic reaction. These results are tabulated in Table II. In Table H, formulation A is the isopropanol-water solution of the bicyclo-(2.2.1)-hept-5-ene-2-carbinylnicotinate.

1 Time after application at which erythema rating at least 1.0.

means? SKIN TEMPERATURE The skin temperature studies clearly illustrate the superiority of the bicyclo-(2.2.1)-hept--ene-2-carbinyl nicotinate over methyl salicylate and methyl nicotinate. The relative activity of these compounds and two commercial balms in this respect is shown in Table III. Formulations B and C in Table III are the same as those previously described.

Table 111 Temperature Rise/Time After Application F., minutes) Analgesic Compound Bioyclo-(2.2.1)-hept-5-ene-2- carbinylnicotinate 1 3. 6 2. 9 1. 8 1. 1 0. 9 O. 9 Methyl Nicotinate 2. 9 1. 1 0. 0 Methyl Salicylate 1. 1. 6 0.7 0.0 Formulation B 2. 5 1. 1 0. 5 O. 4 Formulation O u 2. 5 1. 7 0. 5 0.0

1 5 solution in isopropanol-water (1:1).

A maximum increase in temperature of 3.6 F. was produced in the skin at about 30 minutes after application. All of the other preparations in Table III reached a maximum temperature increase in slightly less than 30 minutes, but in no case did the temperature exceed the temperature produced by the bicyclo nicotinate compound.

Skin temperatures were measured with a thermistor temperature measuring device, sensitive to changes of at least 0.018 F. The formulation was applied to a one square inch skin area on the outer aspect of the upper arm. The resulting temperature rise was measured as the difference between the test spot and a control spot on the other arm. Basal temperatures were first obtained on both arms before the application of the formulations. Basal temperatures at periodic times after the application of the formulation were determined by measuring the temperature of a similar spot on the opposite arm using a third thermistor. In order to avoid errors, the measuring devices were taped in place and moved only for the application of the test formulations.

The results of toxicity measurements by intraperitoneal are, respectively, 1225 and 500.

Only very minor amounts of the compound of this invention need be employed in the analgesic compositions. Generally, for practical utility the analgesic preparation should contain at least about 0.5% by weight of bicyclo- (2.2.1) hept S-ene-Z-carbinylnic'otinate. Less may be used, particularly when combined with other analgesics. Ordinarily the use of as much as 5% of this active ingredient in the analgesic preparation would be wasteful. Increasing the concentration of the bicyclo-(2.2.l)-hept-5- one-2-carbinylnicotinate from 0.5% to 2.5% produced only a slight effect on the degree of erythema observed. From the standpoint of economics and effectiveness, analgesic preparations containing from 0.5% to 2.5% of the compound of this invention are preferred.

The bicyclo (2.2.1) hept S-ene-Z-carbinylnicotinate may be compounded with liquids and semisolid and solid vehicles conventionally employed in analgesic lotions, liniments and balms. Examples of suitable vehicles for the formulation of such analgesic compositions are alcohols, such as isopropanol and ethyl alcohol; mineral oil; squalene; limonene; polyalcohols, such as glycerol, including glycols such as ethylene glycol and propylene glycol; petrolatum; licosane; fatty acid esters of polyethylene glycol, such as polyethylene glycol monostearate; and vanishing creams. These are illustrative of substantially inert materials applicable to skin which may serve as .a vehicle or carrier for the bicyclo nicotinate ester in analgesic preparations. Various embodiments of such preparations utilizing the compound of this invention will be obvious to those skilled in the art and accordingly, it is to be understood that all materials disclosed are to be interpreted as illustrative and not in a limiting sense.

The bicyclo (2.2.1) hept 5-ene-2-carbinylnicotinate may be simply prepared by well-known esterification methods. For example, bicyclo-(2.2.1)-hept-5-ene-2-carbinol (sometimes alternatively referred to as bicyclo- (2.2.1) hept 5 ene-2-rnethylol) may be reacted with nicotinic acid in the presence of boron trioxide as a catalyst at a temperature within the range of 150 C. to 200 C. The bicycloheptenecarbinol starting material acts as a solvent and preferably should be present in an amount greater than a 1:1 molar ratio with the nicotinic acid.

FOREIGN PATENTS 260,159 10/ 26 Great Britain.

IRVING MARCUS, Primary Examiner.

D. T. MCCUTCHEN, WALTER A. MODANCE,

? Examiners. 

